Mendelian randomization analyses explore the relationship between cathepsins and lung cancer.
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ABSTRACT:
SUBMITTER: Li J
PROVIDER: S-EPMC10560205 | biostudies-literature | 2023 Oct
REPOSITORIES: biostudies-literature
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Mendelian randomization analyses explore the relationship between cathepsins and lung cancer.
Li Jialin J Tang Mingbo M Gao Xinliang X Tian Suyan S Liu Wei W
Communications biology 20231007 1
Lung cancer, a major contributor to cancer-related fatalities worldwide, involves a complex pathogenesis. Cathepsins, lysosomal cysteine proteases, play roles in various physiological and pathological processes, including tumorigenesis. Observational studies have suggested an association between cathepsins and lung cancer. However, the causal link between the cathepsin family and lung cancer remains undetermined. This study employed Mendelian randomization analyses to investigate this causal ass ...[more]
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Project description:BackgroundMultiple studies have confirmed the significant role of cathepsins in the development and progression of digestive system tumors. However, further investigation is needed to determine the causal relationships.MethodsWe conducted a two-sample bidirectional Mendelian randomization (MR) study using pooled data from a genome-wide association study (GWAS) to assess the causal associations between nine cathepsins (cathepsin B, E, F, G, H, L2, O, S, and Z) and six types of digestive system tumors, including hepatocellular carcinoma (HCC), pancreatic cancer (PCa), biliary tract cancer (BTC), colorectal cancer (CRC), gastric carcinoma (GC), and esophageal cancer (EC). We employed the following methods including inverse variance weighting (IVW), MR-Egger, weighted median (WM), Cochran's Q, MR-PRESSO, MR-Egger intercept test and leave-one-out sensitivity analysis. The STROBE-MR checklist for the reporting of MR studies was used in this study.ResultsThe risk of HCC increased with high levels of cathepsin G (IVW: p = 0.029, odds ratio (OR) = 1.369, 95% confidence interval (CI) = 1.033-1.814). Similarly, BTC was associated with elevated cathepsin B levels (IVW: p = 0.025, OR = 1.693, 95% CI = 1.070-2.681). Conversely, a reduction in PCa risk was associated with increased cathepsin H levels (IVW: p = 0.027, OR = 0.896, 95% CI = 0.812-0.988). Lastly, high levels of cathepsin L2 were found to lower the risk of CRC (IVW: p = 0.034, OR = 0.814, 95% CI = 0.674-0.985).ConclusionOur findings confirm the causal relationship between cathepsins and digestive system tumors, which can offer valuable insights for the diagnosis and treatment of digestive system tumors.
| S-EPMC10999587 | biostudies-literature
Project description:BackgroundParkinson's disease (PD), the second most prevalent neurodegenerative condition, has a multifaceted etiology. Cathepsin-cysteine proteases situated within lysosomes participate in a range of physiological and pathological processes, including the degradation of harmful proteins. Prior research has pointed towards a potential link between cathepsins and PD; however, the precise causal relationship between the cathepsin family and PD remains unclear.MethodsThis study employed univariate and multivariate Mendelian randomization (MR) analyses to explore the causal relationship between the nine cathepsins and Parkinson's disease (PD) risk. For the primary analysis, genome-wide association study (GWAS) summary statistics for the plasma levels of the nine cathepsins and PD was obtained from the INTERVAL study and the International Parkinson's Disease Genomics Consortium. GWAS for PD replication analysis were obtained from the FinnGen consortium, and a meta-analysis was performed for the primary and replication analyses to evaluate the association between genetically predicted cathepsin plasma levels and PD risk. After identifying significant MR estimates, genetic co-localization analyses were conducted to determine whether shared or distinct causal variants influenced both cathepsins and PD.ResultsElevated cathepsin B levels were associated with a decreased risk of PD in univariate MR analysis (odds ratio [OR] = 0.890, 95% confidence interval [CI]: 0.831-0.954, pFDR = 0.009). However, there was no indication that PD affected cathepsin B levels (OR = 0.965, 95% CI: 0.858-1.087, p = 0.852). In addition, after adjusting for the remaining cathepsins, cathepsin B levels independently and significantly contributed to the reduced risk of PD in multivariate MR analysis (OR = 0.887, 95% CI: 0.823-0.957, p = 0.002). The results of the replication MR analysis with the FinnGen GWAS for PD (OR = 0.921, 95% CI: 0.860-0.987, p = 0.020) and meta-analysis (OR = 0.905, 95% CI: 0.862-0.951, p < 0.001) were consistent with those of the primary analysis. Colocalization analysis did not provide any evidence of a shared causal variant between cathepsins and PD (PP.H4.abf = 0.005).ConclusionThis genetic investigation supports the hypothesis that cathepsin B exerts a protective effect against PD. The quantification of cathepsin B levels could potentially serve as a predictive biomarker for susceptibility to PD, providing new insights into the pathomechanisms of the disease and possible interventions.
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Project description:BackgroundObservational studies have suggested a potential link between cathepsins and major salivary gland neoplasms (MSGNs), but the causality of this relationship remains uncertain. Mendelian randomization (MR) is a significant genetic method that employs single nucleotide polymorphisms (SNPs) as instrumental variables (IVs). This approach reduces confounding effects, enabling the analysis of causal relationships between exposure traits and outcome diseases. This study aimed to explore the causal links between cathepsins and MSGNs by utilizing MR analysis.MethodsIn this research, we collected IVs associated with 11 different types of cathepsins (including cathepsins D, L1, B, E, F, G, H, O, S, L2, and Z) from the Medical Research Council (MRC) integrative epidemiology unit (IEU) open genome-wide association studies (GWAS) database. Data for cathepsins D and L1 were sourced from the SCALLOP consortium, which included 21,758 Europeans identified via the Olink proximity extension assay (PEA). Cathepsins B, E, F, G, H, O, S, L2, and Z were obtained from the INTERVAL study involving 3,301 European participants using the SOMAscan assay. We also collected data on benign major salivary gland neoplasms (BMSGNs) from the FinnGen database, consisting of 3,353 cases and 450,380 controls, and information on major salivary gland carcinomas (MSGCs) from the UK Biobank, which included 105 cases and 456,243 controls. Diagnostic criteria for both BMSGNs and MSGCs followed the international statistical classification of diseases and related health problems 10th revision (ICD-10) classification. A comprehensive bidirectional MR study was executed employing diverse methodologies, including inverse variance weighted (IVW), MR-Egger regression, weighted median, and weighted mode. Additionally, sensitivity analyses were conducted to emphasize the solidity of the study.ResultsIncreased levels of cathepsin F (CTSF), cathepsin O (CTSO), and cathepsin L2 (CTSL2) were associated with a higher risk of BMSGNs (CTSF: IVW: P=0.01, odds ratio (OR) =1.12, CTSO: IVW: P=0.02, OR =1.14; CTSL2: IVW: P=0.01, OR =1.17). Additionally, no causal association was found between cathepsins and MSGCs. Reverse MR analyses did not establish a causal relationship between BMSGNs and various cathepsins. However, it did reveal that a higher risk of MSGCs was associated with lower levels of CTSL2 (IVW: P=0.01, beta =-0.046).ConclusionsThe study presents compelling evidence of a correlation between elevated CTSF, CTSO, and CTSL2 levels and an increased risk of BMSGNs. Elevated CTSF, CTSO, and CTSL2 levels may serve as significant biomarkers for diagnosing BMSGNs definitively. Conversely, reduced levels of CTSL2 provide a novel foundation for diagnosing MSGCs and differentiating them from BMSGNs. Moreover, CTSF, CTSO, and CTSL2 represent potential new targets for therapeutic intervention in BMSGNs and MSGCs.
| S-EPMC11635577 | biostudies-literature
Project description:BackgroundObservational studies reported an association between psoriasis and risk of lung cancer. However, whether psoriasis is causally associated with lung cancer is unclear.MethodsGenetic summary data of psoriasis were retrieved from two independent genome-wide association studies (GWAS). Genetic information of lung cancer was retrieved from GWAS of International Lung Cancer Consortium. A set of quality control steps were conducted to select instrumental tools. We performed two independent two-sample Mendelian randomization (MR) analyses and a meta-analysis based on the two independent MR estimates to assess the causal relationship between psoriasis and lung cancer (LUCA) as well as its subtypes, squamous cell carcinoma (LUSC) and adenocarcinoma (LUAD).ResultsBetween-SNP heterogeneity was present for most MR analyses, whereas horizontal pleiotropy was not detected for all MR analyses. Multiplicative random-effect inverse variance weighted (IVW-MRE) method was therefore selected as the primary MR approach. Both IVW-MRE estimates from the two independent MR analyses suggested that there was no significant causal relationship between psoriasis and LUCA as well as its histological subtypes. Sensitivity analyses using other four MR methods gave similar results. Meta-analysis of the two IVW-MRE derived MR estimates yielded an odds ratio (OR) of 1.00 (95% CI 0.95-1.06) for LUCA, 1.01 (95% CI 0.93-1.08) for LUSC, and 0.97 (95% CI 0.90-1.06) for LUAD.ConclusionOur results do not support a genetic association between psoriasis and lung cancer and its subtypes. More population-based and experimental studies are warranted to further dissect the complex correlation between psoriasis and lung cancer.
| S-EPMC9814449 | biostudies-literature
Project description:Research suggests that cathepsins, due to their extensive mechanisms of action, may play a crucial role in cardiomyopathies. However, further studies are necessary to establish causality. This study aims to investigate the causal relationship between cathepsins and various types of cardiomyopathies. This study investigated causal associations between 9 cathepsins and cardiomyopathies, including their subtypes: hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy, and restrictive cardiomyopathy, using pooled data from genome-wide association studies. The analyses employed inverse variance weighted (IVW), Mendelian randomization (MR)-Egger, and weighted median methods for univariable MR, reverse MR, and multivariable MR to estimate causality. For sensitivity analyses, we applied Cochran Q test, MR-PRESSO, MR-Egger intercept test, and the leave-one-out method to ensure the robustness and reliability of our findings. Univariable MR analyses indicated that elevated levels of cathepsin E were associated with an increased risk of overall cardiomyopathy (IVW: P = .045, odds ratio [OR] = 1.078, 95% confidence interval [CI] = 1.002-1.160). Conversely, higher levels of cathepsin B were linked to a reduced risk of HCM (IVW: P = .037, OR = 0.856, 95% CI = 0.740-0.990), and higher cathepsin O levels were causally related to a reduced risk of HCM (IVW: P = .04, OR = 0.810, 95% CI = 0.662-0.991). Reverse MR analyses indicated that a higher risk of HCM was causally related to increased levels of cathepsin E (IVW: P = .038, OR = 1.024, 95% CI = 1.001-1.047). Multivariable MR analyses showed that increased cathepsin E levels still correlated with increased overall cardiomyopathy, even after the addition of other types of cathepsins (IVW: P = .0165, OR = 1.005, 95% CI = 1.0176-1.1901), while cathepsin O levels remained causally related to a reduced risk of HCM (IVW: P = .0053, OR = 0.7183, 95% CI = 0.5692-0.9065). Cathepsin L2 was also found to be associated with an increased risk of restrictive cardiomyopathy (IVW: P = .0374, OR = 2.1337, 95% CI = 1.0450-4.3565). This study demonstrates the causal relationship between cathepsins E, B, L2, O and the development of cardiomyopathy. The findings may be crucial for early diagnosis, prognosis prediction, molecular classification, and identifying potential therapeutic targets for cardiomyopathy.
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Project description:BackgroundHepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are two major types of primary liver cancer (PLC). Earlier research has indicated a potential link between cathepsins and liver cancer. Nonetheless, there have been limited clinical trials examining the connection between cathepsins and PLC. Therefore, we conducted a two-sample Mendelian randomization (MR) study to evaluate the causal relationship between cathepsins and PLC.MethodsData from genome-wide association studies (GWAS) focusing on cathepsins was collected. Additionally, summary data for GCST90018803 (Hepatic bile duct cancer, HBDC), and GCST90018858 (related to hepatic cancer, HC), were employed in the discovery and validation phases of the study, respectively. The inverse variance weighted (IVW) method was served as the primary analytical method in our Mendelian randomization (MR) study, supplemented by the MR-Egger, weighted median, simple mode, and weighted mode methods. To assess heterogeneity and pleiotropy, we conducted the MR-Egger intercept test, Cochran's Q test, as well as the MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) analysis, along with the leave-one-out analysis. After that, bioinformatic analysis based on the Gene Expression Omnibus (GEO) databases were utilized, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis were utilized for exploring the underlying mechanisms. Additionally, protein-protein docking was employed to confirm the interaction between related proteins.ResultsThe results showed that cathepsin F (CTSF), was causally associated with HBDC. CTSF decrease the risk of HBDC (OR = 0.826, 95% CI 0.711-0.959, P = 0.012). CTSF may play protective roles in patients with HBDC. No heterogeneity or pleiotropy was observed. Additionally, the expression of CTSF genes is lower in patients with HBDC, GO and KEGG functional enrichment analysis revealed CTSF were mainly related to cell cycle, and P53 pathway in HBDC. Docking results showed that CTSF had good binding ability with MDM2, the most well-established negative regulator of p53.ConclusionThis study provided new evidence of the relationship between CTSF and HBDC, suggesting that CTSF plays an inhibition role in HBDC progression. CTSF could be a novel and effective way to for HDBC treatment.
| S-EPMC11889323 | biostudies-literature
Project description:BackgroundLung cancer is a highly prevalent neoplastic disease in various regions of the world, but the mechanism of its occurrence, development, and metastasis is not clear. Different hormone levels have different potential roles in the occurrence, development, and metastasis of lung cancer, but the association between hormone levels and lung cancer is not clear.ObjectiveThis study aims to explore the causal relationship between hormone levels and lung cancer using Mendelian randomization. Sensitivity and heterogeneity tests were conducted to ensure the reliability of the results, offering insights into the prevention, diagnosis, and treatment of lung cancer.MethodsWe employed a two-sample Mendelian randomization (MR) analysis using large-scale publicly available genome-wide association studies (GWAS) data to assess the causal relationship between hormone levels and lung cancer. We explored the causal relationship between 15 hormones and three subtypes of lung cancer. The inverse variance weighted (IVW) method was used as the primary analysis, while MR-Egger, weighted median, weighted mode, and simple median were applied as supplementary methods. Sensitivity and heterogeneity tests were conducted to ensure the robustness of the findings.ResultsWe identified six hormone levels to be significantly associated with lung squamous cell carcinoma (LUSC): total testosterone, oestradiol, thyrotropin-releasing hormone, insulin, parathyroid hormone, and glucocorticoid. Among them, total testosterone, estradiol, and thyrotropin-releasing hormone were negatively correlated with morbidity. Insulin, prolactin levels, and parathyroid hormone were positively correlated with morbidity. Five hormone levels were significantly associated with lung adenocarcinoma (LUAD): luteinizing hormone, thyroid hormones, insulin, prolactin levels, and parathyroid hormone. Luteinizing hormone and thyroid hormones were negatively correlated with morbidity, while insulin, prolactin levels, and parathyroid hormone were positively correlated with morbidity. Similarly, five hormone levels were linked to small cell lung cancer (SCLC): total testosterone, luteinizing hormone, estradiol, PTHrP, and insulin. Total testosterone and luteinizing hormone were negatively correlated with morbidity, while estradiol, Parathyroid Hormone-Related Peptide (PTHrP), and insulin were positively correlated with morbidity. Several hormones were associated with different subtypes of lung cancer. Insulin was significantly associated with all three types of lung cancer. Testosterone showed positive effects in LUSC and SCLC, and estradiol had varying effects, with a negative correlation in SCLC and a positive correlation in LUSC. Testosterone and estradiol were not significantly associated with LUAD. Luteinizing hormone showed positive effects in LUAD and SCLC, and parathyroid hormone showed negative effects in LUSC and LUAD.ConclusionThis study demonstrates significant causal relationships between specific hormone levels and various types of lung cancer, providing valuable insights for prevention, diagnosis, and treatment strategies of lung cancer.
| S-EPMC11864934 | biostudies-literature
Project description:ObjectiveThe purpose of this study was to verify whether there are direct or mediated causal associations between socioeconomic status and lung cancer.MethodsPooled statistics were obtained from corresponding genome-wide association studies. The inverse-variance weighted, weighted median, MR-Egger, MR-PRESSO and contamination-mixture methods were used as supplements to Mendelian randomization (MR) statistical analysis. Cochrane's Q value and the MR-Egger intercept were used for sensitivity analysis.ResultsIn the univariate MR analysis, household income and education had protective effects on overall lung cancer (income: P = 5.46×10-4; education: P = 4.79×10-7) and squamous cell lung cancer (income: P = 2.67×10-3; education: P = 1.42×10-10). Smoking and BMI had adverse effects on overall lung cancer (smoking: P = 2.10×10-7; BMI: P = 5.67×10-4) and squamous cell lung cancer (smoking: P = 5.02×10-6; BMI: P = 2.03×10-7). Multivariate MR analysis found that smoking and education were independent risk factors for overall lung cancer (smoking: P = 1.96×10-7; education: P = 3.11×10-3), while smoking was an independent risk factor for squamous cell lung cancer (P = 2.35×10-6). Smoking, education, and household income mediate the effect of BMI on overall lung cancer (smoking 50.0%, education 49.2%, income 25.3%) and squamous cell lung cancer (smoking 34.8%, education 30.8%, income 21.2%). Smoking, education, and BMI mediate the effect of income on overall lung cancer (smoking 13.9%, education 54.8%, BMI 9.4%) and squamous cell lung cancer (smoking 12.6%, education 63.3%, BMI 11.6%). Smoking, BMI, and income mediate the effect of education on squamous cell lung cancer (smoking 24.0%, BMI 6.2%, income 19.4%).ConclusionIncome, education, BMI, and smoking are causally associated with both overall lung cancer and squamous cell lung cancer. Smoking and education are independent association factors for overall lung cancer, while smoking is an independent association factor for squamous cell lung cancer. Smoking and education also play important mediating roles in overall lung cancer and squamous cell lung cancer. No causal relationship was found between multiple risk factors associated with socioeconomic status and lung adenocarcinoma.
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Project description:BackgroundRecently, some observational studies have suggested potential associations between erectile dysfunction (ED) and respiratory function. However, the underlying biological mechanisms and causal relationships between ED and lung function require further investigation. This study aimed to explore the causalities between ED and lung function traits.MethodsSingle-nucleotide polymorphisms (SNPs) for ED were extracted from the Finngen_r7 (1,154 cases and 94,024 controls), and the summary statistics of respiratory function were extracted from the UK Biobank (UKB) (n=321,047). We utilized several Mendelian randomization (MR) methods to mitigate the impact of weak instrument bias and pleiotropy. To address potential confounding effects, multivariable MR (MVMR) analyses were also conducted, adjusting for demographic factors and respiratory conditions. Moreover, recently developed latent causal variable (LCV) modeling was also performed to enhance the robustness of the findings.ResultsTotally 15 SNPs robustly associated with ED were included. We found that higher risk of ED was associated with decreased of forced expiratory volume in the first second (FEV1) [odds ratio (OR) 0.992, 95% confidence interval (CI): 0.986, 0.997, P=0.003], as was the case for forced vital capacity (FVC) (OR 0.994, 95% CI: 0.989, 1.000, P=0.04), peak expiratory flow (PEF) (OR 0.990, 95% CI: 0.990, 0.990, P=0.01) and FEV1/FVC ratio (OR 0.991, 95% CI: 0.985, 0.997, P=0.002). After adjusting for confounding factors, ED only demonstrated causal effects on FEV1/FVC ratio. Notably, the LCV analysis provided additional support for the positive causal impact of ED on FEV1 and FVC. Conversely, reverse MR analysis did not reveal compelling evidence for a causal effect of lung function on ED.ConclusionsOur study suggests a potential causal relationship between higher ED susceptibility and reduced respiratory function, as indicated by decreased FEV1, FVC, PEF, and the FEV1/FVC ratio. The results enhanced understanding of the intricate interrelationships between ED and lung function.
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Project description:IntroductionBipolar disorder is a psychiatric condition characterized by the coexistence of depression and mania. Diagnosis of this disorder can be challenging due to limited pathologic and experimental tools. Treatment compliance is often poor due to medication side effects. Although cathepsin is known to play a significant role in diseases such as tumors and osteoporosis, its role in psychiatric disorders is not yet fully understood.ObjectiveThe aim of this study was to investigate the relationship between cathepsin in the blood circulation and bipolar disorder.MethodsThe causal relationship between cathepsin and different subtypes of bipolar affective disorder was explored using bidirectional Mendelian randomization analysis and multivariate analysis.ResultsIt was found that cathepsin H level was a protective factor for type II bipolar disorder. No potential causal relationship was found between cathepsin H and type I bipolar disorder, but cathepsin B changes with the development of type I bipolar disorder. A causal relationship was found between cathepsin H and cerebral dopamine neurotrophic factor.ConclusionsIn conclusion, cathepsin H may be a diagnostic target for bipolar II disorder and may play a guiding role in clinical diagnosis. Cathepsin H may have an effect on BD through cerebral dopamine neurotrophic factor.
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